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Allen C. Ho, MD
Professor of Ophthalmology, Sidney Kimmel Medical College and Thomas Jefferson University, Philadelphia
Lejla Vajzovic, MD, FASRS
Associate Professor of Ophthalmology with Tenure, Adult and Pediatric Vitreoretinal Surgery and Diseases, Duke University Eye Center, Durham, North Carolina
Although it may seem like science fiction, gene therapy—the introduction or removal of genetic material or the modification of gene expression to achieve a therapeutic benefit—is already a reality in many fields of medicine.
With more than 30 FDA-approved gene and cell therapies available for clinical use1 and over 2,000 ongoing clinical trials exploring a range of gene and cell therapies across all sectors of medicine,2 countless patients around the world are already benefiting from these strategies. Within ophthalmology, there is one FDA-approved gene therapy for the treatment of patients with RPE65 mutation-associated retinal dystrophy,1 and there are more than 20 ongoing ocular gene therapy trials.2-4 Due to the one-time nature of gene therapy, these trials collect multiple years of data on safety and outcomes.
The human eye has some unique characteristics that make it an opportune site for gene therapy. For example, the eye is small, self-contained, and has relative immune privilege. As well, the eye is easily accessible, both for interventions and for monitoring for potential adverse effects. For these reasons, ocular gene therapy has attracted significant research interest, potentially providing new treatment options for patients. Research being done within the realm of inherited retinal diseases offers to address prominent treatment gaps. Moreover, gene therapy may also be applicable for treating common retinal diseases, such as age-related macular degeneration and other retinal pathologies. Because genetic material that codes for a therapeutic protein can be introduced to targeted cells at the back of the eye—in essence enabling retinal cells to produce their own medicine—gene therapy has the transformative potential to ease treatment burden, extend the duration of effect, and reduce patient compliance as a factor in the outcome.
Drs. Allen Ho and Lejla Vajzovic explain the interest in gene therapy in ophthalmology, how it is applicable for common retinal diseases, and what we know about safety.
1. Why is the eye an interesting place for gene therapy application?
2:05
2. How is gene therapy applicable for common retinal diseases?
3:06
3. What do we know about the safety of gene therapy?
1:35
1. FDA. Approved Cellular and Gene Therapy Products. Available at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products (Accessed 12/6/2023)
2. American Society of Gene + Cell Therapy. ASGCT Clinical Trials Finder. Available at: https://asgct.careboxhealth.com (Accessed 12/7/23)
3. Drag S, Dotiwala F, Upadhyay AK. Gene therapy for retinal degenerative diseases: progress, challenges, and future directions. Invest Ophthalmol Vis Sci. 2023;64(7):39.
4. Arabi F, Mansouri V, Ahmadbeigi N. Gene therapy clinical trials, where do we go? An overview. Biomed Pharmacother. 2022;153:113324.
Learn more about how and why gene therapy is being studied in ophthalmology and how it may hold promise for advancing the standard of care in common retinal disease.
Gene therapy is defined as the introduction or removal of genetic material or the modification of gene expression to achieve a therapeutic benefit. There are 3 main types of gene therapy: gene addition, gene editing, and RNA modification.
Gene Addition1 involves introducing genetic material into a cell to:
A strand of exogenous DNA or RNA is introduced to a cell.
The new gene is incorporated into the cell.
The gene can now induce protein production.
Gene Editing2 involves altering the sequence of an endogenous gene via targeted insertion, replacement, or deletion of DNA base pairs. It can be used to:
A designed guide molecule finds a target DNA strand.
An enzyme causes a targeted break in DNA at the appropriate location.
The gene can now induce protein production.
RNA Modification3-5 involves delivering genetic material to encode for an engineered RNA that recognizes and modifies a cellular RNA target. Examples include:
Micro RNA degrades or binds to mRNA and blocks translation.
Small nuclear RNA facilitate an exonskipping pattern.
Edited mRNA sequence changes the sequence of the translated protein.
1. Petrich J, Marchese D, Jenkins C, et al. Gene replacement Therapy: a primer for the health-system pharmacist. J Pharm Pract. 2020;33(6):846-855.
2. Mander ML, Gersbach CA. Genome-editing technologies for gene and cell therapy. Mol Ther. 2016;24(3):430-446.
3. Adachi H, Hengesbach M, Yu YT, Morais P. From antisense RNA to RNA modification: therapeutic potential of RNA-based technologies. Biomedicines. 2021;9(5):550.
4. Lam JK, Chow MY, Zhang Y, Leung SW. siRNA Versus miRNA as therapeutics for gene silencing. Mol Ther Nucleic Acids. 2015;4(9):e252.
5. Berger A, Maire S, Gaillard M-C, et al. mRNA trans-splicing in gene therapy for genetic diseases. Wiley Interdiscip Rev RNA. 2016;7(4):487-498.
Since gene therapy is still a newer modality, there are some misconceptions that are encountered while talking about gene therapy.
Click/tap the card to see the answer and more information.
Gene editing is the only form of gene therapy that alters the host genome.
Hear from Dr. Vajzovic below.
More Information:
While some viral vectors do integrate their transgenes into the host genome, gene addition with adeno-associated viral vector (AAV) gene therapy functions differently by introducing a sequence that exists alongside a person's native DNA primarily in the form of an episome. The episome allows the transgene to independently participate in protein synthesis separately and distinctly from endogenous DNA.
Viral Vector — A disease-disabled virus that functions as a vehicle to deliver genetic material to a cell; comprised of three main parts:
Tropism — A virus' or viral vector’s affinity for a particular cell type.
Transduction — The process by which genetic material is introduced into a cell by a virus or viral vector.
Episome — Exogenous genetic material inside a cell that is separate from endogenous DNA, and can replicate independently.
The goal of gene therapy is to introduce genetic material to achieve a therapeutic effect. This is accomplished by packaging the new genetic material, or transgene,The genetic material encoding the final product (ie, protein). into a delivery vehicle called a vector. A common type of vector used for retinal diseases is a viral vectorA disease-disabled virus that functions as a vehicle to deliver genetic material to a cell; comprised of three main parts: capsid, promoter, and transgene.—a virus that has been modified to remove its ability to replicate. Viral vectors are specifically selected for each gene therapy application based on their individual affinity, or tropism,A virus' or viral vector’s affinity for a particular cell type. for the targeted host cell type.
Within ophthalmology, adeno-associated viral vectors (AAVs) have gained significant interest because they demonstrate high tropism for retinal cells. More specifically, the AAV8 serotype has attracted significant research interest based on pre-clinical evidence that it is effective at delivering genetic material, also known as transduction,The process by which genetic material is introduced into a cell by a virus or viral vector. into photoreceptors and retinal pigment epithelium (RPE).1,2
One type of gene therapy approach, gene addition, is being investigated to treat common retinal diseases like age-related macular degeneration and diabetic retinopathy, where a patient’s retinal cells make the therapeutic protein needed to treat the disease. Once inside the cell, the transgene harnesses the cell’s natural process of protein synthesis to produce a therapeutic protein.
Cross-section of a viral vector showing the capsid,The outer shell of a virus that encloses its genetic material. promoter,A region of DNA that initiates transcription of a gene into RNA. and transgene.
Drs. Allen Ho and Lejla Vajzovic discuss viral vectors, how they are used, and which types are currently being studied for ophthalmic applications.
1. Ding K, Shen J, Hafiz Z, et al. AAV8-vectored suprachoroidal gene transfer produces widespread ocular transgene expression. J Clin Invest. 2019;129(11):4901-4911.
2. Vandenberghe LH, Bell P, Maguire AM, et al. Dosage thresholds for AAV2 and AAV8 photoreceptor gene therapy in monkey. Sci Transl Med. 2011;3(88):88ra54.
Scroll to explore how gene therapy works and a therapeutic protein is created.
An AAV vector binds to a receptor at the surface of the cell membrane ...
Cell Membrane
... and enters the cell via endocytosis.
The vector is trafficked to the nucleus.
Nucleus
Once inside the nucleus, the DNA is released.
The single-stranded DNA is converted to double-stranded DNA.
Formation of an episome allows the exogenous DNA to remain independent of the cell's endogenous chromosome.
Messenger RNA (mRNA) based on the new gene sequence is produced through the process of transcription.
Nucleus
mRNA leaves the nucleus, and it can now be translated to generate the missing, functional, or therapeutic protein.
The therapeutic protein is created.
Watch the video for more information.
Gene therapy can only be effective if it is delivered to the cells of interest. Three routes of administration are currently being investigated for delivery of gene therapy to the retina: subretinal, suprachoroidal, and intravitreal. Ongoing studies investigating the safety and efficacy of gene delivery with each route of administration will help determine the viability for potential clinical use. Among the many factors in the risk-benefit profile of each is whether surgery is involved, thereby adding the potential for intraoperative risks.
1.
Subretinal
Surgical Procedure
Play the video for more information on the subretinal route of administration.
2.
Suprachoroidal
In-Office Procedure
Play the video for more information on the suprachoroidal route of administration.
3.
Intravitreal
In-Office Procedure
Play the video for more information on the intravitreal route of administration.
Drs. Allen Ho and Lejla Vajzovic explore the routes of delivery currently being investigated for gene therapy for the retina.
1. What are the routes of delivery for gene therapy?
1:57
2. Is subretinal delivery of gene therapy a difficult surgery?
1:46
1. FDA list of approved cell and gene therapies. Accessed 7 May 2024. Available at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products
2. Vandenberghe LH, Bell P, Maguire AM, et al. Dosage thresholds for AAV2 and AAV8 photoreceptor gene therapy in monkey. Sci Transl Med. 2011;3(88):88ra54.
3. Seitz IP, Michalakis S, Wilhelm B, et al. et al. Superior retinal gene transfer and biodistribution profile of subretinal versus intravitreal delivery of AAV8 in nonhuman primates. Invest Ophthalmol Vis Sci. 2017;58(13):5792-5801.
4. Kovacs KD, Ciulla TA, and Kiss S. Advancements in ocular gene therapy delivery: vectors and subretinal, intravitreal, and suprachoroidal techniques. Expert Opin Biol Ther. 2022;22(9):1193-1208.
5. Ghoraba HH, Akhavanrezayat A, Karaca I, et al. Ocular gene therapy: A literature review with special focus on immune and inflammatory responses. Clin Ophthalmol. 2022:16:1753-1771.
6. Yeh S, Kurup SK, Wang RC, et al. Suprachoroidal injection of triamcinolone acetonide, CLS-TA, for macular edema due to noninfectious uveitis: A randomized, Phase 2 Study (DOGWOOD). Retina. 2019;39(10):1880-1888.
7. Ding K, Shen J, Hafiz Z, et al. AAV8-vectored suprachoroidal gene transfer produces widespread ocular transgene expression. J Clin Invest. 2019;129(11):4901-4911.
8. Yin L, Grennberg K, Hunter JJ, et al. Intravitreal injection of AAV2 transduces macaque inner retina. Invest Ophthalmol Vis Sci. 2011;52(5):2775-2783.
Since gene therapy is still a newer modality, there are some misconceptions that are encountered while talking about gene therapy.
Click/tap the card to see the answer and more information.
Gene therapy is also being tested as an intervention in common diseases.
Hear from Dr. Ho below.
More Information:
While gene therapy offers the exciting potential to treat various forms of heritable diseases affecting the retina, it is also being tested as an intervention in common diseases, such as age-related macular degeneration and diabetic retinopathy.
There are multiple types of gene therapy, but not all of them aim to fix a missing or nonfunctional gene. In fact, it is possible to introduce exogenous DNA that codes for a therapeutic protein, thus offering the potential to slow the progression of various retina diseases.
Sponsored By Medical Affairs:
Allen C. Ho, MD
Director of Retina Research, Wills Eye Hospital, Philadelphia
Professor of Ophthalmology, Sidney Kimmel Medical College and Thomas Jefferson University, Philadelphia
Chief Medical Editor, Retina Today
achomd@gmail.comFinancial disclosure: Consultant/Grant Funding (Adverum, Apellis, Asclepix, Clearside, Genentech/Roche, Gyroscope, Iveric Bio/Astellas, Kodiak, Lineage, Regenxbio)
Lejla Vajzovic, MD, FASRS
Director, Duke Surgical Vitreoretinal Fellowship Program, Duke University Eye Center, Durham, North Carolina
Associate Professor of Ophthalmology with Tenure, Adult and Pediatric Vitreoretinal Surgery and Diseases, Duke University Eye Center, Durham, North Carolina
Editorial Advisory Board Member, Retina Today
lejla.vajzovic@duke.eduFinancial disclosure: Consultant (Abbvie/Allergan, Alcon, Alimera Sciences, Apellis, Bausch + Lomb, Beaver-Visitec International, BMC, Clearside Biomedical, Coherus Biosciences, DORC, Genentech/Roche, Guidepoint, Gyroscope, Iveric Bio/Astellas, Janssen, Novartis, Ocugen, Ocular Therapeutix, Oculus Surgical, OcuTerra, Outlook Therapeutics, Regenxbio); Honoraria (Evolve Medical Education, Vindico Medical Education); Investigator (AGTC, Alcon, Aldeyra, Genentech/Roche, Heidelberg, NEI, Novartis, Ocular Therapeutix, Regenxbio); Research Grants (Gyroscope, Heidelberg)
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